3-hydroxybutyrate alone or in combination for use in the treatment of critical care treatment

ABSTRACT

This invention relates generally to methods and compositions for the treatment or prevention of critical illness myopathy and critical illness polyneuropathy and of critical illness myopathy and critical illness polyneuropathy caused by critical illnesses including sepsis, severe sepsis, severe sepsis with septic shock, and particularly to the use of a combination of parenteral or enteral feeding with a 3-hydroxybutyrate.

TECHNICAL FIELD

This invention relates generally to methods and compositions for thetreatment for amelioration or prevention of sepsis, severe sepsis,severe sepsis with septic shock, critical illness myopathy and criticalillness polyneuropathy and particularly to the use of a combination ofparenteral or enteral feeding with a carboxylic acid.

BACKGROUND

Critical illness is defined as any acute medical condition necessitatingvital organ support without which death would be imminent. Whetherevoked by sepsis, severe sepsis, septic shock, trauma, major surgery, orother critical illnesses, patients can suffer from critical illnessmyopathy and/or critical illness polyneuropathy, a clinicalmanifestation referred to as intensive care unit (ICU) acquired weakness(ICUAW) (Kress J P, Hall J B 2014 NEJM 370(17): 1626-35). Prevalence ofICUAW varies according to the study population, but up to 80% of ICUpatients appear to suffer from muscle wasting and/or muscle weakness.ICUAW is associated with impaired weaning from mechanical ventilation,delayed rehabilitation and prolonged hospitalization, late death andgreater impaired functional outcome of survivors. Parenteral provisionof macronutrients during acute critical illness does not prevent muscleweakness and may in fact exert deleterious effects via furthersuppression of autophagic myofiber quality control (Hermans et al, 2013Lancet Respir Med 1(8):621-9; Derde S et al, 2012 Crit Care Med40(1):79-89).

However, despite the major advances of the past several decades in theunderstanding of critical illnesses including sepsis, severe sepsis,severe sepsis with septic shock, critical illness myopathy and criticalillness polyneuropathy, there is still no effective treatment to treatthese conditions or reduce the symptoms such as ICUAW associated withthem. There is, therefore, a need for new methods and compositions forthe treatment of sepsis, severe sepsis, severe sepsis with septic shock,critical illness myopathy and critical illness polyneuropathy.

SUMMARY

It is, therefore, an object of the present invention to provide methodsand compositions for treating sepsis, severe sepsis, septic shock,critical illness myopathy and critical illness polyneuropathy. It isanother object of the invention to decrease the morbidity and morepreferably the muscle weakness associated with sepsis, severe sepsis,septic shock, critical illness myopathy and critical illnesspolyneuropathy.

In accordance with another aspect of the instant invention, the abovemethods are used for the treatment of symptoms associated with acritical illness which includes, but is not limited to sepsis, severesepsis, septic shock, critical illness myopathy and critical illnesspolyneuropathy.

This invention was based in part on the discovery that critical illnessand/or sepsis, severe sepsis, septic shock, critical illness myopathyand critical illness polyneuropathy can be prevented, treated or cured,at least to a certain extent, by a composition containing a carboxylicacid, more preferably 3-hydroxybutyric acid in combination with enteralor parenteral feeding. Further scope of applicability of the presentinvention will become apparent from the detailed description givenhereinafter. However, it should be understood that the detaileddescription and specific examples, while indicating preferredembodiments of the invention, are given by way of illustration only,since various changes and modifications within the spirit and scope ofthe invention will become apparent to those skilled in the art from thisdetailed description. It is to be understood that both the foregoinggeneral description and the following detailed description are exemplaryand explanatory only and are not restrictive of the invention, asclaimed.

The invention relates to a method of treatment for ameliorating orpreventing of critical illness myopathy (2016/17 ICD-10-CM DiagnosisCode G72.81), critical illness polyneuropathy (2016/17 ICD-10-CMDiagnosis Code G62.81) or critical illness neuromyopathy (CINM)comprising administering to a subject in need thereof compositioncomprising 1) an 3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyricacid, (S)-3-Hydroxybutyric acid or enantiomeric mixture, or apharmaceutically acceptable or under food law acceptable salt or apharmaceutically acceptable or under food law acceptable ester thereof.Critical illness polyneuropathy and critical illness myopathy areoverlapping syndromes of diffuse, symmetric, flaccid muscle weaknessoccurring in critically ill patients and involving all extremities andthe diaphragm with relative sparing of the cranial nerves. An example ofa for present invention suitable salt is pharmaceutically acceptable orunder food law acceptable (R)-3-hydroxybutyric sodium salt or sodium(S)-3-hydroxybutyrate and an example of a for the present inventionsuitable ester is pharmaceutically acceptable or under food lawacceptable (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Examples of a forpresent invention suitable administering to a subject in need thereof isa parenteral administration of a parenteral composition comprising 1) an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof or enteraladministration of a enteral composition comprising 1) an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof. The delivery canbe continuous or as bolus.

One aspect of the invention described herein relates to a method oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) comprising administering to a subject inneed thereof composition comprising 1) an 3-hydroxybutyrate, itsenantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid orenantiomeric mixture, or a pharmaceutically acceptable or under food lawacceptable salt or a pharmaceutically acceptable or under food lawacceptable ester thereof, wherein the treatment with the3-hydroxybutyrate is carried out with a continuous or multiple doseregime at a dose range of 0.08 g/kg patient body weight to 4.13 g/kgpatient body weight per 24 hours.

Another aspect of the invention described herein relates to a method oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) comprising administering to a subject inneed thereof composition comprising 1) an 3-hydroxybutyrate, itsenantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid orenantiomeric mixture, or a pharmaceutically acceptable or under food lawacceptable salt or a pharmaceutically acceptable or under food lawacceptable ester thereof, wherein the treatment with the3-hydroxybutyrate is carried out with a continuous or multiple doseregime at a dose range of 0.8 mmol/kg patient body weight to 39.7mmol/kg patient body weight per 24 hours.

Yet another aspect of the invention described herein relates to a methodof treatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) comprising administering to a subject inneed thereof composition comprising 1) an 3-hydroxybutyrate, itsenantiomer (R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid orenantiomeric mixture, or a pharmaceutically acceptable or under food lawacceptable salt or a pharmaceutically acceptable or under food lawacceptable ester thereof, wherein the treatment with the3-hydroxybutyrate is carried out with a continuous or bolus, parenteralor enteral dose range of 0.08 g/kg to 4.13 g/kg patient body weight per24 hours. In some embodiments this treatment for ameliorating orpreventing of critical illness myopathy (2016/17 ICD-10-CM DiagnosisCode G72.81), critical illness polyneuropathy (2016/17 ICD-10-CMDiagnosis Code G62.81) or critical illness neuromyopathy (CINM) iscarried out with 3-hydroxybutyrate as a continuous or bolus, parenteralor enteral dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kgpatient body weight per 24 hours. In some other embodiment thistreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) is carried out with 3-hydroxybutyrate thatis administered to a patient at a daily dose of about 1.6 mmol/kg to79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7 mmol/kg, morepreferably of about 3.2 mmol/kg.

Applicant has discovered that the particular compositions describedherein provide unexpectedly high muscle force improvement andeffectively overcome critical illness myopathy or neuromyopathy orcritical illness polyneuropathy in combinational therapy formulatedtogether and in individual dosage amounts or formulated separately andin individual dosage amounts with a chemical energy providingmacronutrient or caloric organic compound comprising at least onemacronutrient member of one of the macronutrient groups 1) amacronutrient group consisting of amino acid, peptide and protein orcombination thereof and 2) a macronutrient group consisting of fattyacid, glycerol, glyceride and triglyceride or combination thereof and 3)a macronutrient group consisting of monosaccharide, disaccharide,oligosaccharide and polysaccharide or combination thereof. One object ofthe invention described herein thus concerns a method for treating suchfor ameliorating or preventing of critical illness myopathy (2016/17ICD-10-CM Diagnosis Code G72.81), critical illness polyneuropathy(2016/17 ICD-10-CM Diagnosis Code G62.81) or critical illnessneuromyopathy (CINM) comprising administering to a subject in needthereof such composition comprising an 3-hydroxybutyrate, wherein the3-hydroxybutyrate is in combinational therapy formulated together and inindividual dosage amounts or formulated separately and in individualdosage amounts with a chemical energy providing macronutrient or caloricorganic compound comprising at least one macronutrient member of one ofthe macronutrient groups 1) a macronutrient group consisting of aminoacid, peptide and protein or combination thereof and 2) a macronutrientgroup consisting of fatty acid, glycerol, glyceride and triglyceride orcombination thereof and 3) a macronutrient group consisting ofmonosaccharide, disaccharide, oligosaccharide and polysaccharide orcombination thereof. Another object of the invention described hereinthus concerns a method for treating such for ameliorating or preventingof critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM) comprisingadministering to a subject in need thereof such composition comprisingan 3-hydroxybutyrate, wherein the 3-hydroxybutyrate is in combinationaltherapy formulated together and in individual dosage amounts orformulated separately and in individual dosage amounts with a chemicalenergy providing macronutrient or caloric organic compound comprising atleast one macronutrient member of two macronutrient groups each of themacronutrient groups 1) a macronutrient group consisting of amino acid,peptide and protein or combination thereof and 2) a macronutrient groupconsisting of fatty acid, glycerol, glyceride and triglyceride orcombination thereof and 3) a macronutrient group consisting ofmonosaccharide, disaccharide, oligosaccharide and polysaccharide orcombination thereof. Yet another object of the invention describedherein thus concerns a method for treating such for ameliorating orpreventing of critical illness myopathy (2016/17 ICD-10-CM DiagnosisCode G72.81), critical illness polyneuropathy (2016/17 ICD-10-CMDiagnosis Code G62.81) or critical illness neuromyopathy (CINM)comprising administering to a subject in need thereof such compositioncomprising an 3-hydroxybutyrate, wherein the 3-hydroxybutyrate is incombinational therapy formulated together and in individual dosageamounts or formulated separately and in individual dosage amounts with achemical energy providing macronutrient or caloric organic compoundcomprising at least one macronutrient member of each of the threemacronutrient groups 1) a macronutrient group consisting of amino acid,peptide and protein or combination thereof and 2) a macronutrient groupconsisting of fatty acid, glycerol, glyceride and triglyceride orcombination thereof and 3) a macronutrient group consisting ofmonosaccharide, disaccharide, oligosaccharide and polysaccharide orcombination thereof.

The present therapies have been shown to be highly effective in criticalillness of lean subjects. A certain aspect of the invention describedherein thus concerns a method for treating such for ameliorating orpreventing of critical illness myopathy (2016/17 ICD-10-CM DiagnosisCode G72.81), critical illness polyneuropathy (2016/17 ICD-10-CMDiagnosis Code G62.81) or critical illness neuromyopathy (CINM)comprising administering to a subject in need thereof such compositioncomprising an 3-hydroxybutyrate, wherein the patient has a BMI under24.9, wherein the patient is a normal weight patient with a BMI between18.5 and 24.9 or wherein the patient is an underweight patient with aBMI under 18.5.

The composition of treatment of present invention can further comprisingone or more pharmaceutically acceptable or under food law acceptableadjuvants, carriers, excipients, and/or diluents.

The present disclosure relates in an aspect also to a 3-hydroxybutyrateof the groups consisting of an 3-hydroxybutyrate, its enantiomer(R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomericmixture, or a pharmaceutically acceptable or under food law acceptablesalt or a pharmaceutically acceptable or under food law acceptable esterthereof for use in a treatment to prevent or ameliorate critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) in a subject in need thereof. In a certainembodiment these pharmaceutically acceptable or under food lawacceptable salts are (R)-3-hydroxybutyric sodium salt or sodium(S)-3-hydroxybutyrate. In yet another embodiment the pharmaceuticallyacceptable or under food law acceptable ester is (R)-3-hydroxybutyl(R)-3-hydroxybutyrate. A particular aspect of present invention is thatthe 3-hydroxybutyrate for use in a treatment to prevent or amelioratecritical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM) in a subject in needthereof, whereby the treatment with the 3-hydroxybutyrate is carried outwith a continuous or multiple dose regime at a dose range of 0.08 g/kgpatient body weight to 4.13 g/kg patient body weight per 24 hours.Another particular aspect of present invention is that the3-hydroxybutyrate for use in a treatment to prevent or amelioratecritical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM) in a subject in needthereof, wherein the treatment with the 3-hydroxybutyrate is carried outwith a continuous or multiple dose regime at a dose range of 0.8 mmol/kgpatient body weight to 39.7 mmol/kg patient body weight per 24 hours.Yet another particular aspect of present invention is that the3-hydroxybutyrate for use in a treatment to prevent or amelioratecritical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM) in a subject in needthereof, wherein the treatment with the 3-hydroxybutyrate is carried outwith a continuous or bolus, parenteral or enteral dose range of 0.08g/kg to 4.13 g/kg patient body weight per 24 hours. Yet anotherparticular aspect of present invention is that the 3-hydroxybutyrate foruse in a treatment to prevent or ameliorate critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) in a subject in need thereof, wherein thetreatment with the 3-hydroxybutyrate is carried out with a continuous orbolus, parenteral or enteral dose range of 0.8 mmol/kg patient bodyweight to 39.7 mmol/kg patient body weight per 24 hours. Yet anotherparticular aspect of present invention is that the 3-hydroxybutyrate foruse in a treatment to prevent or ameliorate critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) in a subject in need thereof, wherein the3-hydroxybutyrate is administered to a patient at a daily dose of about1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7mmol/kg, more preferably of about 3.2 mmol/kg.

The applicants found that the treatment with the 3-hydroxybutyrate isdrastically efficient in the critical ill subjects which also receivechemical energy providing macronutrient or caloric organic compounds.

Yet another aspect of present invention is the 3-hydroxybutyrate ofpresent invention for use treatment for ameliorating or preventing ofcritical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM), wherein the3-hydroxybutyrate is in combinational therapy formulated together and inindividual dosage amounts or formulated separately and in individualdosage amounts with a chemical energy providing macronutrient or caloricorganic compound comprising at least one macronutrient member of one ofthe three macronutrient groups or of two of the three macronutrientgroups each or of each of the three macronutrient groups 1) amacronutrient group consisting of amino acid, peptide and protein orcombination thereof and 2) a macronutrient group consisting of fattyacid, glycerol, glyceride and triglyceride or combination thereof and 3)a macronutrient group consisting of monosaccharide, disaccharide,oligosaccharide and polysaccharide or combination thereof.

A lean critically ill subject was found to be in high need for the3-hydroxybutyrate treatment of present invention and the presenttherapies have been shown to be highly effective in critical ill leansubjects. It is thus an object of present invention to use to provide a3-hydroxybutyrate for use treatment for ameliorating or preventing ofcritical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD10-CM Diagnosis Code G62.81)or critical illness neuromyopathy (CINM), wherein the patient has a BMIunder 24.9. Another object of present invention is to provide a3-hydroxybutyrate for use treatment for ameliorating or preventing ofcritical illness myopathy (2016/17 ICD10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM), wherein the patient isa normal weight patient with a BMI between 18.5 and 24.9. Yet anotheraspect of present invention is to provide a 3-hydroxybutyrate for usetreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), wherein the patient is an underweightpatient with a BMI under 18.5. This 3-hydroxybutyrate of the compositioncomprising 3-hydroxybutyrate for use according to present invention, canfurther comprise one or more pharmaceutically acceptable or under foodlaw acceptable adjuvants, carriers, excipients, and/or diluents.

The present disclosure relates in another aspect also to a pack or acomposition for use in a combinational therapy of treating or preventingof critical illness myopathy (2016/17 ICD-10-CM Diagnosis Code G72.81),critical illness polyneuropathy (2016/17 ICD-10-CM Diagnosis CodeG62.81) or critical illness neuromyopathy (CINM), the pack orcomposition comprising an 3-hydroxybutyrate, its enantiomer(R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomericmixture, or a pharmaceutically or under food law acceptable salt, forinstance (R)-3-hydroxybutyric sodium salt or sodium(S)-3-hydroxybutyrate, or a pharmaceutically acceptable or under foodlaw acceptable ester thereof, for instance (R)-3-hydroxybutyl(R)-3-hydroxybutyrate and a macronutrient mixture comprising at leastone macronutrient member of one of the three macronutrient groups or oftwo of the three macronutrient groups each or of each of the threemacronutrient groups 1) a macronutrient group consisting of amino acid,peptide and protein or combination thereof and 2) a macronutrient groupconsisting of fatty acid, glycerol, glyceride and triglyceride orcombination thereof and 3) a macronutrient group consisting ofmonosaccharide, disaccharide, oligosaccharide and polysaccharide orcombination thereof. This pack may be for use in a combinational therapyof treating or preventing of a disorder of c critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), whereby the disorder is evoked, induced orenhanced by disorder of the group consisting of sepsis (2016/17ICD-10-CM Diagnosis Code A41.9), severe sepsis (2016/17 ICD-10-CMDiagnosis Code R65.2), severe sepsis with septic shock (2016/2017ICD-10-CM Diagnosis Code R.65.21) or it may be for use in acombinational treatment to prevent or ameliorate muscle weakness (2017ICD-10-CM Diagnosis Code M62.81) evoked, induced or enhanced by acritical illness myopathy 2016/17 (ICD-10-CM Diagnosis Code G72.81) orcritical illness neuromyopathy (2016/17 ICD-10-CM Diagnosis Code G62.81)disorder.

Such pack or composition of present invention for use for use in acombinational therapy of treating or preventing of critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), can comprise the 3-hydroxybutyrate andsaid macronutrient mixture formulated together and in individual dosageamounts.

In a particular aspect the pack or composition for use in acombinational therapy of treating or preventing of critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), is so designed that the treatment with3-hydroxybutyrate can be carried out with a continuous or multiple doseregime at a dose range of 0.08 g/kg patient body weight to 4.13 g/kgpatient body weight per 24 hours.

In yet another a particular aspect the pack or composition for use in acombinational therapy of treating or preventing of critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), is so designed that the treatment with3-hydroxybutyrate can be carried out with a continuous or multiple doseregime at a dose range of 0.8 mmol/kg patient body weight to 39.7mmol/kg patient body weight per 24 hours.

In yet another a particular aspect the pack or composition for use in acombinational therapy of treating or preventing of critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), is so designed that the treatment with3-hydroxybutyrate can be carried out with a continuous or bolus,parenteral or enteral dose range of 0.08 g/kg to 4.13 g/kg patient bodyweight per 24 hours.

In yet another a particular aspect the pack or composition for use in acombinational therapy of treating or preventing of critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), is so designed that the treatment with3-hydroxybutyrate can be carried out with a continuous or bolus,parenteral or enteral dose range of 0.8 mmol/kg patient body weight to39.7 mmol/kg patient body weight per 24 hours.

The present invention provides also a pack or composition for use oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) whereby the pack comprises an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof and wherein isdesigned for 3-hydroxybutyrate administration to a patient at a dailydose of about 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6mmol/kg to 31.7 mmol/kg, more preferably of about 3.2 mmol/kg.

The present invention provides also a pack or composition for use oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) whereby the pack comprises an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof, wherein the3-hydroxybutyrate is present in said composition in an amount equivalentto 1-70 grams.

The present invention provides also a pack or composition for use oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) whereby the pack comprises an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof, wherein the3-hydroxybutyrate is present in said composition in an amount equivalentto 5-60 grams.

The present invention provides also a pack or composition for use oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) whereby the pack comprises an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof, wherein the3-hydroxybutyrate is present in said composition in an amount equivalentto 10-50 grams.

The present invention provides also a pack or composition for use oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) whereby the pack comprises an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof, wherein the3-hydroxybutyrate is present in said composition in an amount equivalentto 0.05-10 grams.

The present invention provides also a pack or composition for use oftreatment for ameliorating or preventing of critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM) whereby the pack comprises an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt or a pharmaceuticallyacceptable or under food law acceptable ester thereof, wherein the3-hydroxybutyrate is present in said composition in an amount equivalentto 0.08-4.13 grams. In a particular aspect said composition isformulated for systemic administration.

In yet another embodiment of the invention, the composition is usedwithout causing or without aggravating a hepato-pancreato-biliarydisorder. In a more particular embodiment the composition is usedwithout causing or without aggravating fatty liver or withoutaggravating or causing nonalcoholic steatohepatitis (NASH) (2017ICD-10-CM Diagnosis Code K75.81).

DESCRIPTION OF THE DRAWINGS

The present invention will become more fully understood from thedetailed description given herein below and the accompanying drawingswhich are given by way of illustration only, and thus are not limitativeof the present invention, and wherein:

FIG. 1 Mice body composition. (a) Body weight after 5 days ofCLP-induced critical illness (ANOVA p≤0.01). (b) Loss of body weightduring the 5-day experiment (ANOVA p=0.4). (c) End body fat mass,measured by DEXA (ANOVA p≤0.01). (d) Loss in body fat mass during 5 daysof critical illness (ANOVA p≤0.01). White, healthy lean mice (n=8); darkgray, fed lean CLP mice (n=7); light gray, fasted lean CLP mice (n=9);white dotted, healthy obese mice (n=9); dark gray dotted, fed obese CLPmice (n=10); light gray dotted, fasted obese CLP mice (n=9). [DEXA:dual-energy-X-ray-absorptiometry, CLP: cecal ligation and puncture,ctrl: healthy control animals, fed: parenterally fed, fast: fasted]

FIG. 2 Mice skeletal muscle mass and cross-sectional area. (a) Dryweight of the m. tibialis anterior (ANOVA p≤0.01). (b) Dry weight of them. soleus (ANOVA p≤0.01). White, healthy lean mice (n=8); dark gray, fedlean CLP mice (n=7); light gray, fasted lean CLP mice (n=9); whitedotted, healthy obese mice (n=9); dark gray dotted, fed obese CLP mice(n=10); light gray dotted, fasted obese CLP mice (n=9). (c) Skeletalmuscle myofiber cross-sectional area (ANOVA p≤0.01). Cross-sectionalarea is categorized in blocks of 1000 pixels for each animal. The graphdisplays smoothed curves of the percentage of myofibers in eachcategory, gray dotted line, healthy animals; black line, CLP mice.Statistical difference reflects mean myofiber cross-sectional area. Fedand fasted CLP mice were grouped as they were similar (p=0.3 in leanCLP; p=0.4 in obese CLP). [CLP: cecal ligation and puncture, ctrl:healthy control animals, fed: parenterally fed, fast: fasted]

FIG. 3 Mice skeletal muscle atrophy and autophagy. (a) Relative mRNAexpression of Fbxo32 (ANOVA p≤0.01). (b) Relative mRNA expression ofTrim63 (ANOVA p≤0.01). (c) Activity of the 20S-proteasome (ANOVA p=0.9).(d) Cathepsin activity (ANOVA p=0.4). (e) Relative mRNA expression ofAtg7 (ANOVA p≤0.01). (f) Relative mRNA expression of Atg5 (ANOVAp≤0.01). (g) LC3-II/LC3-1 protein ratio, as detected with western blot(ANOVA p=0.4). (h) Protein level of p62, measured with western blot(ANOVA p≤0.01). Gene expression data are expressed normalized to Rn18sgene expression and as a fold change of the mean of the lean healthycontrols. Protein levels are presented as fold change of the mean oflean healthy controls. White, healthy lean mice (n=8); dark gray, fedlean CLP mice (n=7); light gray, fasted lean CLP mice (n=9); whitedotted, healthy obese mice (n=9); dark gray dotted, fed obese CLP mice(n=10); light gray dotted, fasted obese CLP mice (n=9). [dw: dry weight,CLP: cecal ligation and puncture, ctrl: healthy control animals, fed:parenterally fed, fast: fasted]

FIG. 4 Mice muscle and hepatic triglyceride content. (a) Triglyceridecontent of skeletal muscle tissue (Mann-Whitney p≤0.01). (b) Hepatictriglyceride content (Mann-Whitney p≤0.01). White, healthy lean mice(n=8); dark gray, fed lean CLP mice (n=7); light gray, fasted lean CLPmice (n=9); white dotted, healthy obese mice (n=9); dark gray dotted,fed obese CLP mice (n=10); light gray dotted, fasted obese CLP mice(n=9). [dw: dry weight, CLP: cecal ligation and puncture, ctrl: healthycontrol animals, fed: parenterally fed, fast: fasted]

FIG. 5 Mice fatty acid metabolism. (a) Serum fatty acid concentration(ANOVA p≤0.01). (b) Relative mRNA expression of Cd36 (ANOVA p≤0.01). (c)Relative Hmgcs2 mRNA expression (ANOVA p≤0.01). (d) Ketone body serumconcentration (ANOVA p≤0.01). Gene expression data are expressednormalized to Rn18s gene expression and as a fold change of the mean ofthe lean healthy controls. White, healthy lean mice (n=8); dark gray,fed lean CLP mice (n=7); light gray, fasted lean CLP mice (n=9); whitedotted, healthy obese mice (n=9); dark gray dotted, fed obese CLP mice(n=10); light gray dotted, fasted obese CLP mice (n=9). [CLP: cecalligation and puncture, ctrl: healthy control animals, fed: parenterallyfed, fast: fasted, 3-HB: 3-hydroxybutyric acid]

FIG. 6 Mice glycerol metabolism. (a) Serum glycerol concentrations(ANOVA p≤0.01). (b) Relative mRNA levels of Aqp9 (ANOVA p=0.4). (c)Relative mRNA levels of Gk (ANOVA p=0.04). Gene expression data areexpressed normalized to Rn18s gene expression and as a fold change ofthe mean of the lean healthy controls. White, healthy lean mice (n=8);dark gray, fed lean CLP mice (n=7); light gray, fasted lean CLP mice(n=9); white dotted, healthy obese mice (n=9); dark gray dotted, fedobese CLP mice (n=10); light gray dotted, fasted obese CLP mice (n=9).[CLP: cecal ligation and puncture, ctrl: healthy control mice, fed:parenterally fed, fast: fasted]

FIG. 7 Mice muscle force. Ex vivo force measurements of the m. extensordigitorum longus (EDL). (a) Dry weight (ANOVA p=0.04). (b) Peak tetanicmuscle tensions (ANOVA p≤0.01). (c) Recovery from fatigue after 10minutes, as percentage of initial muscle force (ANOVA p≤0.01). White,healthy lean mice, pair-fed (n=17); dark gray, fed lean CLP mice (n=15);white dotted, healthy obese mice, pair-fed (n=15); dark gray dotted, fedobese CLP mice (n=15). [CLP: cecal ligation and puncture, ctrl: healthycontrol animals, PF, pair-fed, fed: parenterally fed]

FIG. 8 Muscle cross-sectional area in prolonged critically ill patients.(a) m. vastus lateralis myofiber cross-sectional area of in vivobiopsies from lean (BMI≤25; n=51) and overweight/obese (BMI>25; n=51)prolonged critically ill patients and lean (n=11) and overweight/obese(n=9) healthy controls. (b) m. rectus abdominis myofiber cross-sectionalarea of postmortem biopsies from lean (n=43) and overweight/obese (n=43)prolonged critically ill patients and lean (n=4) and overweight/obese(n=7) healthy controls. Cross-sectional area is categorized in blocks of1000 pixels. The graph displays smoothed curves of the percentagemyofibers in each category, split up for critically ill patients (blackline) and healthy controls (gray dotted line). Statistical differencereflects a change in proportion of small (<2000) myofibers.

FIG. 9. Effect of 3-hydroxybutyrate administration on muscle weakness inprolonged critically ill mice. Ex vivo force measurements of theextensor digitorum longus (EDL) muscle. White, healthy control mice(n=15); light gray, parenterally fed critically ill mice (n=16); darkgray, parenterally fed critically ill mice receiving daily subcutaneousinjections of 3-hydroxybutyrate (n=14); dark gray dotted, fastedcritically ill mice receiving daily subcutaneous injections of3-hydroxybutrate (n=14). [PN=parenteral nutrition;3HB=3-hydroxybutyrate].

FIG. 10. Effect of 3-hydroxybutyrate injections on 5-day mortality inprolonged critically ill mice. Black line, healthy control mice (15/15survivors); gray line, parenterally fed critically ill mice (17/20survivors); dash dot line; parenterally fed critically ill micereceiving 3-hydroxybutyrate (17/21 survivors); dotted line, fastedcritically ill mice receiving 3-hydroxybutyrate (14/22 survivors).[PN=parenteral nutrition; 3HB=3-hydroxybutyrate].

FIG. 11. Effect of 3-hydroxybutyrate administration on muscle wasting inprolonged critically ill mice. (a) Dry weight of the extensor digitorumlongus (EDL) muscle. (b) Dry weight of the tibialis anterior muscle.White, healthy control mice (n=15); light gray, parenterally fedcritically ill mice (n=17); dark gray, parenterally fed critically illmice receiving daily subcutaneous injections of 3-hydroxybutyrate(n=17); dark gray dotted, fasted critically ill mice receiving dailysubcutaneous injections of 3-hydroxybutrate (n=14). [PN=parenteralnutrition; 3HB=3-hydroxybutyrate].

FIG. 12. Effect of a ketogenic diet on muscle weakness in prolongedcritically ill mice. Ex vivo force measurements of the extensordigitorum longus (EDL) muscle. White, healthy control mice (n=17); lightgray, parenterally fed critically ill mice (n=16); dark gray, criticallyill mice on a lipid-rich, ketogenic diet (n=15). [PN=parenteralnutrition; Lipid=lipid-rich, ketogenic diet].

FIG. 13. Effect of a ketogenic diet on muscle wasting in prolongedcritically ill mice. (a) Dry weight of the extensor digitorum longus(EDL) muscle. (b) Dry weight of the tibialis anterior muscle. White,healthy control mice (n=24); light gray, parenterally fed critically illmice (n=23); dark gray, critically ill mice on a lipid-rich, ketogenicdiet (n=23). [PN=parenteral nutrition; Lipid=lipid-rich, ketogenicdiet].

FIG. 14. Circulating 3-hydroxybutyrate in prolonged critically ill mice.White, healthy control mice (n=24); light gray, parenterally fedcritically ill mice (n=23); dark gray, critically ill mice on alipid-rich, ketogenic diet (n=23). [PN=parenteral nutrition;Lipid=lipid-rich, ketogenic diet].

FIG. 15. Effect of a ketogenic diet on liver steatosis in prolongedcritically ill mice. Liver steatosis, presented as the hepatictriglyceride content. White, healthy control mice (n=24); light gray,parenterally fed critically ill mice (n=23); dark gray, critically illmice on a lipid-rich, ketogenic diet (n=23). [PN=parenteral nutrition;Lipid=lipid-rich, ketogenic diet].

FIG. 16 Effect of ketone supplementation with different compositions ofparenteral nutrition on muscle wasting in prolonged critically ill mice.(A) Wet weight of the extensor digitorum longus (EDL) muscle. (B) Exvivo absolute force measurements of the EDL muscle. (C) Ex vivo specificforce measurements of the EDL muscle. White, healthy control mice(n=15); pink, TPN+3HB critically ill mice (n=16); brown, LIPID+3HBcritically ill mice (n=16); green, AA+3HB critically ill mice (n=16);blue, GLUC+3HB critically ill mice (n=17). $, p?0.05 different fromhealthy controls.

DETAILED DESCRIPTION Definitions

In describing the present invention, the following terms will beemployed, and are intended to be defined as indicated below.

The caloric target in the meaning of this application is a calorictarget calculated as the caloric need times the Corrected Ideal BodyWeight. The formula for calculating Ideal Body Weight for a femalepatient is 45.5+[0.91×(height in cm−152.4)] and for a male patient50+[0.91×(height in cm−152.4)]. If BMI<18.5, the Corrected Ideal BodyWeight is (Ideal Body Weight+Actual Body Weight)/2, if 27≤BMI≥18.5, theCorrected Ideal Body Weight is the Ideal Body Weight, if BMI>27, theCorrected Ideal Body Weight is the Ideal Body Weight×1.2. The caloricneed for a female patient>60 years is 24 kcal/kg/day, the caloric needfor a male patient>60 years is 30 kcal/kg/day, the caloric need for afemale patient≤60 years is 30 kcal/kg/day, the caloric need for a malepatient≤60 years it is 36 kcal/kg/day.

It must be noted that the caloric calories required for pediatric ICUpatients differ from adults, for instance caloric calories required forpediatric ICU patients is 100 Cal/kg/day for a body weight 0-10 kg,1000+(50/kg over 10 kg) for a body weight of 10-20 kg, and 1500+(20/kgover 20 kg) for a body weight>20 kg. It has to be understood thatlikewise the claimed ratio chemical energy providing macronutrient orcaloric organic compounds in the medical compositions are adaptable forpediatric ICU patients.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise.

The term “about,” particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

The terms “subject,” “individual,” and “patient,” are usedinterchangeably herein and refer to any animal, including, withoutlimitation, humans and other primates, including non-human primates suchas chimpanzees and other apes and monkey species; farm animals such ascattle, sheep, pigs, goats and horses; domestic mammals such as dogs andcats; laboratory animals including rodents such as mice, rats and guineapigs; birds, including domestic, wild and game birds such as chickens,turkeys and other gallinaceous birds, ducks, geese, and the like, andtransgenic animals. In some cases, the methods of the invention find usein experimental animals, in veterinary applications, and in thedevelopment of animal models for disease. Preferably, the patient is ahuman.

The term “parenterally” or “parenteral administration” as used hereinmeans administration of a product by means of injection, such asinjection into a vein (intravenous administration), into a muscle(intramuscular administration), under the skin (subcutaneousadministration) or intraperitoneal injection.

The term “enterally” or “enteral administration” as used herein refersto the introduction of a product into the stomach or intestines, such asby tube feeding or by peroral administration (such as eating). Inparticular enteral administration refers to the introduction of aproduct into the stomach or intestines via a tube.

The term “Sepsis” has been described under 2016/17 ICD-10-CM DiagnosisCode A41.9 in the ICD-10-CM Diagnosis Codes and means the presence of abacteria or their toxins in the blood or tissues.

The term “Severe sepsis” has been described under 2016/17 ICD-10-CMDiagnosis Code R65.2 in the ICD-10-CM Diagnosis Codes and means sepsisassociated with organ dysfunction distant from the site of infection.

The term “Severe sepsis with septic shock” has been described under2016/2017 ICD-10-CM Diagnosis Code R.65.21 and means life-threateninglow blood pressure (shock) due to sepsis The term “Critical illnessmyopathy” has been described under 2016/17 ICD-10-CM Diagnosis CodeG72.81 in the ICD-10-CM Diagnosis Codes. The term “Critical illnesspolyneuropathy” has been described under 2016/17 ICD-10-CM DiagnosisCode G62.81 in the ICD-10-CM Diagnosis Codes. Both Critical illnessmyopathy and Critical illness polyneuropathy refers to a syndrome ofdiffuse, symmetric, flaccid muscle weakness occurring in critically illpatients and involving all extremities and the diaphragm with relativesparing of the cranial nerves. Critical illness myopathy and Criticalillness polyneuropathy have similar symptoms and presentations and areoften distinguished largely on the basis of specializedelectrophysiological testing or muscle and nerve biopsy.

In its broadest sense, the term a “critically ill patient”, as usedherein refers to a patient who has sustained or are at risk ofsustaining acutely life-threatening single or multiple organ systemfailure due to disease or injury, a patient who is being operated andwhere complications supervene, and a patient who has been operated in avital organ within the last week or has been subject to major surgerywithin the last week. In a more restricted sense, the term a “criticallyill patient”, as used herein refers to a patient who has sustained orare at risk of sustaining acutely life-threatening single or multipleorgan system failure due to disease or injury, or a patient who is beingoperated and where complications supervene. In an even more restrictedsense, the term a “critically ill patient”, as used herein refers to apatient who has sustained or are at risk of sustaining acutelylife-threatening single or multiple organ system failure due to diseaseor injury. Similarly, these definitions apply to similar expressionssuch as “critical illness in a patient” and a “patient is criticallyill”.

The term “Intensive Care Unit” (herein designated ICU), as used hereinrefers to the part of a hospital where critically ill patients aretreated. Of course, this might vary from country to country and evenfrom hospital to hospital and said part of the hospital may notnecessary, officially, bear the name “Intensive Care Unit” or atranslation or derivation thereof. Of course, the term “Intensive CareUnit” also covers a nursing home, a clinic, for example, a privateclinic, or the like if the same or similar activities are performedthere.

The term “lipid” refers to a fat or fat-like substance that is insolublein polar solvents such as water. The term “lipid” is intended to includetrue fats (e.g. esters of fatty acids and glycerol); lipids(phospholipids, cerebrosides, waxes); sterols (cholesterol, ergosterol)and lipoproteins (e.g. HDL, LDL and VLDL).

The term “BMI” or “body mass index” refers to the ratio of weight(kg)/height (m2) and can be used to define whether a subject isunderweight, normal, overweight, obese or severely obese. Typically,according to WHO criteria, a subject is underweight if he has aBMI<18.5; normal if he has a BMI of 18.5-24.9, overweight if he has aBMI of 25-29.9, class I obese if he has a BMI of 30-34.9, class II obeseif he has a BMI of 35-39.9 and class Ill or severely obese if he has aBMI>40.

As used herein, the terms “treatment,” “treating,” and the like, referto obtaining a desired pharmacologic and/or physiologic effect. Theeffect may be prophylactic in terms of completely or partiallypreventing a disease or symptom thereof and/or may be therapeutic interms of a partial or complete cure for a disease and/or adverse effectattributable to the disease. “Treatment,” as used herein, covers anytreatment of a disease in a mammal, particularly in a human, andincludes: (a) increasing survival time; (b) decreasing the risk of deathdue to the disease; (c) preventing the disease from occurring in asubject which may be predisposed to the disease but has not yet beendiagnosed as having it; (d) inhibiting the disease, i.e., arresting itsdevelopment (e.g., reducing the rate of disease progression); and (e)relieving the disease, i.e., causing regression of the disease, (f)improving the condition of the patient (e.g., in one or more symptoms),etc.

The term “administration” as used herein refers to delivery of at leastone therapeutic agent to a patient.

“Pharmaceutically acceptable or under food law acceptable salt”includes, but is not limited to, amino acid salts, salts prepared withinorganic acids, such as chloride, sulfate, phosphate, diphosphate,bromide, and nitrate salts, or salts prepared from the correspondinginorganic acid form of any of the preceding, e.g., hydrochloride, etc.,or salts prepared with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate,lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate,palmoate, salicylate and stearate, as well as estolate, gluceptate andlactobionate salts. Similarly salts containing pharmaceuticallyacceptable or under food law acceptable cations include, but are notlimited to, sodium, potassium, calcium, aluminum, lithium, and ammonium(including substituted ammonium).

The term “pharmaceutically acceptable or under food law acceptableester” as used herein, either alone or in combination with anothersubstituent, means esters of the carboxylic acid in which any of thecarboxyl functions of the molecule, is replaced by an alkoxycarbonylfunction: in which the R moiety of the ester is selected from alkyl(e.g. methyl, ethyl, n-propyl, tbutyl, n-butyl); alkoxyalkyl (e.g.methoxymethyl); alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g. benzyl);aryloxyalkyl (e.g. phenoxymethyl); aryl (e.g. phenyl), optionallysubstituted with halogen, C1-4 alkyl or C1-4 alkoxy. Other suitableprodrug esters can be found in Design of prodrugs, Bundgaard, H. Ed.Elsevier (1985) incorporated herewith by reference. Suchpharmaceutically acceptable or under food law acceptable esters areusually hydrolyzed in vivo when injected in a mammal and transformedinto the acid form of the carboxylic acid.

As used herein, “a pharmaceutically acceptable or under food lawacceptable carrier medium” includes any and all solvents, diluents,other liquid vehicles, dispersion or suspension aids, surface activeingredients, preservatives, solid binders, lubricants, and the like, assuited to the particular dosage form desired. Remington's PharmaceuticalSciences, Fifteenth Edition, E. W. Martin (Mack Publishing Co., EastonPa. 1975) discloses various vehicles or carriers used in formulatingpharmaceutical compositions and known techniques for the preparationthereof. Except insofar as any conventional carrier medium isincompatible with the compounds of the invention, (such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other component(s) of the pharmaceuticalcomposition), its use is within the scope of the invention.

The Invention

The following detailed description of the invention refers to theaccompanying drawings. The same reference numbers in different drawingsidentify the same or similar elements. Also, the following detaileddescription does not limit the invention. Instead, the scope of theinvention is defined by the appended claims and equivalents thereof.

Several documents are cited throughout the text of this specification.Each of the documents herein (including any manufacturer'sspecifications, instructions etc.) are hereby incorporated by reference;however, there is no admission that any document cited is indeed priorart of the present invention.

The present invention will be described with respect to particularembodiments and with reference to certain drawings but the invention isnot limited thereto but only by the claims. The drawings described areonly schematic and are non-limiting. In the drawings, the size of someof the elements may be exaggerated and not drawn to scale forillustrative purposes. The dimensions and the relative dimensions do notcorrespond to actual reductions to practice of the invention.

Furthermore, the terms first, second, third and the like in thedescription and in the claims, are used for distinguishing betweensimilar elements and not necessarily for describing a sequential orchronological order. It is to be understood that the terms so used areinterchangeable under appropriate circumstances and that the embodimentsof the invention described herein are capable of operation in othersequences than described or illustrated herein.

Moreover, the terms top, bottom, over, under and the like in thedescription and the claims are used for descriptive purposes and notnecessarily for describing relative positions.

It is to be understood that the terms so used are interchangeable underappropriate circumstances and that the embodiments of the inventiondescribed herein are capable of operation in other orientations thandescribed or illustrated herein.

It is to be noticed that the term “comprising” used in the claims,should not be interpreted as being restricted to the means listedthereafter; it does not exclude other elements or steps.

It is thus to be interpreted as specifying the presence of the statedfeatures, integers, steps or components as referred to, but does notpreclude the presence or addition of one or more other features,integers, steps or components, or groups thereof. Thus, the scope of theexpression “a device comprising means A and B” should not be limited tothe devices consisting only of components A and B. It means that withrespect to the present invention, the only relevant components of thedevice are A and B.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiments is included in at least oneembodiment of the present invention. Thus, appearances of the phrases“in one embodiment” or “in an embodiment” in various places throughoutthis specification are not necessarily all referring to the sameembodiments, but may. Furthermore, the particular features, structuresor characteristics may be combined in any suitable manner, as would beapparent to one of ordinary skill in the art from this disclosure, inone or more embodiments.

Similarly it should be appreciated that in the description of exemplaryembodiments of the invention, various features of the invention aresometimes grouped together in a single embodiment, figure, ordescription thereof for the purpose of streamlining the disclosure andaiding the understanding of one or more of the various inventiveaspects. This method of disclosure, however, is not to be interpreted asreflecting an intention that the claimed invention requires morefeatures than are expressly recited in each claim. Rather, as thefollowing claims reflect, inventive aspects lie in less than allfeatures of a single foregoing disclosed embodiment. Thus, the claimsfollowing the detailed description are hereby expressly incorporatedinto this detailed description, with each claim standing on its own as aseparate embodiment of this invention.

Furthermore, while some embodiments described herein include some butnot other features included in other embodiments, combinations offeatures of different embodiments are meant to be within the scope ofthe invention, and form different embodiments, as would be understood bythose in the art. For example, in the following claims, any of theclaimed embodiments can be used in any combination.

In the description provided herein, numerous specific details are setforth. However, it is understood that embodiments of the invention maybe practiced without these specific details.

In other instances, well-known methods, structures and techniques havenot been shown in detail in order not to obscure an understanding ofthis description.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein.

It is intended that the specification and examples be considered asexemplary only.

Each and every claim is incorporated into the specification as anembodiment of the present invention. Thus, the claims are part of thedescription and are a further description and are in addition to thepreferred embodiments of the present invention.

Each of the claims set out a particular embodiments of the invention.

In accordance with the purpose of the invention, as embodied and broadlydescribed herein, the invention is broadly drawn to provide for anenteral or parenteral composition comprising 1) a carboxylic acid and 2)a chemical energy providing macronutrient or caloric organic compound ofthe group consisting of amino acid, peptide, protein, fatty acid,glycerol, glyceride, triglyceride, monosaccharide, disaccharide,oligosaccharide and polysaccharide or combination thereof for use in thetreatment of the physical condition of patient with a disorder of thegroup consisting of sepsis, severe sepsis, severe sepsis with septicshock, critical illness myopathy and critical illness polyneuropathy.

Exemplary carboxylic acids are acetoacetic acid, lactic acid, propionicacid, 3-hydroxypropanoic acid, malonic acid, hydroxypentanoic acid,butyric acid, β-methylbutyric acid, β-hydroxy 3-methylbutyric acid,erythrose, threose, 1,2-butanediol,1,3-butanediol, 2,3-butanediol,1,4-butanediol, hydroxybutyric acid, 3-hydroxybutyric acid,L-β-hydroxybutyric acid, D-β-hydroxybutyric acid, DL-β-hydroxybutyricacid or a pharmaceutically acceptable or under food law acceptable saltor a pharmaceutically acceptable or under food law acceptable esterthereof.

In a preferred embodiment the carboxylic acid is selected from the groupconsisting of acetoacetic acid, hydroxybutyric acid, 3-hydroxybutyricacid and L-β-hydroxybutyric acid or a pharmaceutically acceptable orunder food law acceptable salt or a pharmaceutically acceptable or underfood law acceptable ester thereof.

In a more particular embodiment the carboxylic acid is acetoacetic acid(also diacetic acid); the organic compound with the formulaCH3COCH2COOH. It is the simplest beta-keto acid group, and like othermembers of this class it is unstable. The methyl and ethyl esters, whichare quite stable, are produced on a large scale industrially asprecursors to dyes. Acetoacetic acid is a weak acid. It is ofbiochemical importance in various animals, including humans, as one ofthe endogenous ketone bodies produced by the liver when it breaks downfatty acids into Acetyl-CoA and TCA cycle intermediates are depleted(particularly oxaloacetate, which is formed from pyruvate derived fromglycolysis). It can be viewed as the product of joining two acetic acidmolecules via a condensation reaction that ejects a water molecule inthe process, although that is only one of the ways of forming theacetoacetate molecule. In the human body, a large portion ofacetoacetate is converted to beta-hydroxybutyrate, a rich energy sourcefor the brain, which cannot run directly on fatty acids themselves dueto their poor ability to cross the blood-brain barrier. In the mammalianbody, a large portion of acetoacetate is converted tobeta-hydroxybutyrate.

In yet another particular embodiment the carboxylic acid isβ-Hydroxybutyric acid, also known as 3-hydroxybutyric acid, an organiccompound and a beta hydroxy acid with the formula CH3CH(OH)CH2CO2H; itsconjugate base is beta-hydroxybutyrate, also known as 3-hydroxybutyrate.β-Hydroxybutyric acid is a chiral compound having two enantiomers,D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized andpolymeric derivatives occur widely in nature.

In one embodiment the enteral or parenteral composition is intended foruse in the treatment for preventing or improving muscle weakness ofpatient with a disorder of the group consisting of sepsis, severesepsis, severe sepsis with septic shock, critical illness myopathy andcritical illness polyneuropathy. In other embodiments the enteral orparenteral composition is intended for use in the treatment forpreventing or improving muscle weakness, despite muscle wasting of apatient with a disorder of the group consisting of sepsis, severesepsis, severe sepsis with septic shock, critical illness myopathy andcritical illness polyneuropathy.

In yet another embodiment of the invention, the composition is usedwithout causing or without aggravating a hepato-pancreato-biliarydisorder. In a more particular embodiment the composition is usedwithout causing or without aggravating fatty liver.

In other embodiment of the invention the enteral or parenteralcomposition further comprises a pharmaceutically acceptable or underfood law acceptable carrier.

In one embodiment of the invention the enteral or parenteral compositionhas a total calorie content between 16-106% of the calculated calorictarget for intensive care (ICU) patients.

In one embodiment of the invention the enteral or parenteral compositionhas a total calorie content between 200 to 2000 kcal/l, yet morepreferable between 900 to 1400 kcal/l, yet more preferable 900 to 1300kcal/I, 1100 to 1200 kcal/l.

In another particular embodiment, the composition has a calorie contentof monosaccharide, disaccharide, oligosaccharide, polysaccharide, fattyacid, glycerol, glyceride and/or triglyceride between 600 to 1300kcal/l, yet more preferable between 700 to 1200 kcal/l, yet morepreferable 800 to 1100 kcal/l, 900 to 1000 kcal/l. In another particularembodiment the composition has a calorie content of amino acid, peptideand/or protein between 20 to 330 kcal/l, yet more preferable between 50to 300 kcal/l, yet more preferable 100 to 250 kcal/I and most preferable150 to 200 kcal/l.

In yet another particular embodiment, the composition has a caloriecontent of monosaccharide, disaccharide, oligosaccharide and/orpolysaccharide between 200 to 800 kcal/l, yet more preferable between300 to 800 kcal/l, yet more preferable 400 to 700 kcal/I and mostpreferable 500 to 600 kcal/l.

In yet another particular embodiment, the composition has a caloriecontent of fatty acid, glycerol, glyceride and/or triglyceride between200 to 600 kcal/l, yet more preferable between 250 to 550 kcal/l, yetmore preferable 300 to 500 kcal/I and most preferable 350 to 450 kcal/l.

In another embodiment the fatty acid, glycerol, glyceride and/ortriglyceride provide between 20 to 80%, yet more preferable 25 to 45%and most preferable 30 to 40% of the total calorie content of saidcomposition.

In certain embodiments the carboxylic acid or carboxylate thereof orpharmaceutically acceptable or under food law acceptable salt or apharmaceutically acceptable or under food law acceptable ester thereofis administered to a patient at a daily dose of about 1.6 mmol/kg to79.3 mmol/kg, preferably of about 1.6 mmol/kg to 31.7 mmol/kg, morepreferably of about 3.2 mmol/kg and the additional chemical energyproviding macronutrient or caloric organic compound is administered to apatient at a dose of 10-100% of the calculated caloric target for ICUpatients.

In more particular embodiments this administration is enteral orparenteral, once to several times for one day to several days and in 84%of the patients less than 14 days.

In certain embodiments the composition is used in a treatment of apatient with a BMI under 24.9, more particularly in a treatment of anormal weight patient with a BMI between 18.5 and 24.9 or in thetreatment of an underweight patient with a BMI under 18.5.

In one aspect, the present invention provides a method for preventingand treating sepsis, severe sepsis, severe sepsis with septic shock,critical illness myopathy and critical illness polyneuropathy. Themethod comprises administering the enteric or parenteral compositioncomprising 1) a carboxylic acid and 2) a chemical energy providingmacronutrient or caloric organic compound of the group consisting ofamino acid, peptide, protein, fatty acid, glycerol, glyceride,triglyceride, monosaccharide, disaccharide, oligosaccharide andpolysaccharide or combination thereof. The carboxylic acid can beselected from the group consisting of acetoacetic acid, lactic acid,propionic acid, 3-hydroxypropanoic acid, malonic acid, hydroxypentanoicacid, butyric acid, β-methylbutyric acid, β-hydroxy 3-methylbutyricacid, erythrose, threose, 1,2-butanediol,1,3-butanediol, 2,3-butanediol,1,4-butanediol, hydroxybutyric acid, 3-hydroxybutyric acid andL-β-hydroxybutyric acid or a pharmaceutically acceptable or under foodlaw acceptable salt or a pharmaceutically acceptable or under food lawacceptable ester thereof. In a preferred embodiment the carboxylic acidis selected from the group consisting of acetoacetic acid,hydroxybutyric acid, 3-hydroxybutyric acid and L-β-hydroxybutyric acidor a pharmaceutically acceptable or under food law acceptable salt or apharmaceutically acceptable or under food law acceptable ester thereof.

The caloric target can be calculated as the caloric need times theCorrected Ideal Body Weight.

The formula for calculating Ideal Body Weight for a female patient is45.5+[0.91×(height in cm−152.4)] and for a male patient 50+[0.91×(heightin cm−152.4)]. If BMI<18.5, the Corrected Ideal Body Weight is (IdealBody Weight+Actual Body Weight)/2, if 27≥BMI≥18.5, the Corrected IdealBody Weight is the Ideal Body Weight, if BMI>27, the Corrected IdealBody Weight is the Ideal Body Weight×1.2. The caloric need for a femalepatient>60 years is 24 kcal/kg/day, the caloric need for a malepatient>60 years is 30 kcal/kg/day, the caloric need for a femalepatient≤60 years is 30 kcal/kg/day, the caloric need for a malepatient≤60 years it is 36 kcal/kg/day.

In other embodiments the invention includes method for the treatment forpreventing or improving muscle weakness of patient with a disorder ofthe group consisting of sepsis, severe sepsis, severe sepsis with septicshock, critical illness myopathy and critical illness polyneuropathy,comprising administering an enteric or parenteral composition.

In yet another embodiments the invention includes method for thetreatment for preventing or improving muscle weakness of patient despitemuscle wasting with a disorder of the group consisting of sepsis, severesepsis, severe sepsis with septic shock, critical illness myopathy andcritical illness polyneuropathy, comprising administering an enteric orparenteral composition.

In certain embodiments the method is used in a treatment of a patientwith a BMI under 24.9, more particularly in a treatment of a normalweight patient with a BMI between 18.5 and 24.9 or in the treatment ofan underweight patient with a BMI under 18.5.

In certain embodiments the method further comprises one or morepharmaceutically acceptable or under food law acceptable adjuvants,carriers, excipients, and/or diluents.

Particular and preferred aspects of the invention are set out in theaccompanying independent and dependent claims. Features from thedependent claims may be combined with features of the independent claimsand with features of other dependent claims as appropriate and notmerely as explicitly set out in the claims.

Thus, the claims following the detailed description are hereby expresslyincorporated into this detailed description, with each claim standing onits own as a separate embodiment of this invention.

EXAMPLES

This invention can be further illustrated by the following examples ofpreferred embodiments thereof, although it will be understood that theseexamples are included merely for purposes of illustration and are notintended to limit the scope of the invention unless otherwisespecifically indicated.

Materials and Methods Set-Up of the Animal Model

Diet-induced obesity: Male, 12-week old C57BL/6J mice (Janvier SASChassal, France) received ad libitum standard chow (10% fat, E15745-04,ssniff, Soest, Germany), or ad libitum high-fat diet (45% fat,E15744-34, ssniff) for 12 weeks. Body weight was quantified weekly. Onlyanimals placed on the high-fat diet that reached a body weight above 30g but below 45 g (to avoid morbid obesity-associated metabolicalterations) within the 12 weeks of diet were included in the study.Tail blood glucose measurements indicated that all mice remainednormoglycemic during the obesity-inducing diet (Accu-check, Roche,Basel, Switzerland).

Mice experiment 1: At 24 weeks of age, lean and obese animals wererandomly allocated to “healthy control” (lean healthy mice (n=8) andobese healthy mice (n=9)) or to “CLP.” CLP groups were randomlysubdivided into a fasted-CLP or fed-CLP group. The CLP-induced septiccritical illness model and nutritional protocols of the animals havepreviously been described in detail (Marques et al, 2013 Crit Care17(5):R193). Total body, fat and fat-free mass were quantified with DEXAscans at the start (day −2) and at the end of the 5-day experiment.After 5 days of critical illness, animals were sacrificed bydecapitation, vital organs were removed, snap frozen in liquid nitrogenand stored at −80° C., or preserved in paraformaldehyde. In lean CLPanimals, 9/15 fasted and 7/11 fed mice survived until day 5. In obeseCLP animals, 9/10 fasted and 10/18 fed mice survived until day 5.

Mice experiment 2: We examined muscle force ex vivo in lean anddiet-induced obese CLP mice. The experimental setup was comparable tothat of mice experiment 1. Mice were randomly allocated to “healthycontrol” or “CLP.” As in experiment 1 we had observed that musclewasting occurred irrespective of feeding, we now only comparedparenterally fed with pair-fed lean (n=17) and obese (n=15) healthymice. Until day 5, 15/18 lean and 15/18 obese CLP mice survived. After 5days, animals were deeply anesthetized and the m. extensor digitorumlongus (EDL) was carefully dissected from both hind limbs for ex vivomuscle force measurements.

Mice Body and Tissue Composition and Mass

To control for potential illness- or resuscitation-related changes influid content, dry weight of isolated tissues was obtained by afreeze-drying process. Myofiber cross-sectional area (CSA) wasquantified on digital microscopy images of hematoxylin and eosin stainedparaffin sections with in-house designed algorithms. In addition, thepresence of myofiber degeneration, necrosis and inflammation washistologically evaluated. Triglyceride content of tissues was determinedwith a commercial colorimetric assay (triglyceride quantification kit,Abcam, Cambridge, UK).

Mice Circulating Fatty Acids, Glycerol and Ketone Bodies

Serum concentrations of free fatty acids, glycerol and 3-hydroxybutyrate(3-HB) were determined with commercially available assay kits (freefatty acid fluorometric assay kit, Cayman Chemical Company, Ann Arbor,Mich., USA; glycerol assay kit, Sigma-Aldrich, Saint Louis, Mo., USA;EnzyChrom ketone body assay kit, BioAssay Systems, Hayward, Calif.,USA).

Mice Tissue Gene Expression and Protein Expression Analyses

Messenger RNA of skeletal muscle and liver was isolated and cDNA wasquantified in realtime as previously described with commercial TaqMan®Assays (Applied Biosystems, Carlsbad, Calif., USA). Data were normalizedto ribosomal 18S (Rn18s) gene expression and expressed as fold change ofthe mean of the controls. Microtubule-associated protein 1A/1B-lightchain 3 (LC3)-I, LC3-II (Ab from Sigma-Aldrich) and p62 protein (Ab fromNovus, Littleton, Colo., USA) levels were quantified in m. gastrocnemiuswith Western blots. Data were expressed relative to the means of thecontrols. Commercial kits were used to measure proteasome(20S-proteasome activity assay, InnoZyme) and cathepsin B/L activities(Cathepsin L activity kit, Millipore, Merck KGaA, Darmstadt, Germany) inm. tibialis anterior homogenates.

Patient Studies

Myofiber CSA: In vivo skeletal muscle needle biopsies were obtained fromthe m. vastus lateralis of the m. quadriceps femoris of ICU patients onday 8±1 of ICU stay (Casaer M et al, 2011 NEJM 365(6):506-17; Hermans Get al, 2013 Lancet Respir Med 1(8):621-9). As healthy references, invivo m. vastus lateralis needle biopsies (n=20) were available fromhealthy individuals undergoing minor urological intervention or surgeryfor inguinal herniation. Healthy volunteers had comparable demographicsas ICU patients. From 122 patients of whom myofiber CSA were available(Hermans et al, 2013 Lancet Respir Med 1(8):621-9), we selected 51 leanpatients (BMI≤25 kg/m2) and 51 overweight/obese patients (BMI>25 kg/m2),matched with use of propensity scores obtained by logistic regression(one-to-one nearest neighbor matching without replacement and with acaliper of 0.2). For this propensity score matching, the followingbaseline characteristics were used: gender, age, presence of malignancy,diabetes, APACHE II score on admission, and randomization. Next, weinvestigated postmortem m. rectus abdominis skeletal muscle biopsies,harvested immediately after death, from which myofiber CSA was available(Derde S et al, 2012 Crit Care Med 40(1):79-89). From 148 availablebiopsies, 43 lean and 43 overweight/obese patients were propensity scorematched similarly as the first set. As healthy references, in vivo m.rectus abdominis biopsies (n=11) were available from non-critically illindividuals with comparable demographics.

Muscle weakness: In fully cooperative patients, who were still in theICU on day 8±1, muscle strength was quantified with the MRC sum score(Hermans et al, 2013 Lancet Respir Med 1(8):621-9). To correct for apossible bias by an effect of the randomized intervention on ICU stay, arandom sample of patients discharged from the ICU was assessed in theregular hospital ward on post-randomization day 8±1. Clinically relevantweakness was diagnosed when the MRC sum score was lower than 48. Of the352 patients that were tested on post-admission-day 8±1, 139 lean and139 overweight/obese patients were propensity score matched, similarlyas the first sets. Of the 139 lean patients, 74 patients were tested onthe regular hospital ward, 65 in the ICU. Of the 139 overweight/obesepatients, 76 patients were tested on the ward, 63 in the ICU.

Statistics

Normally distributed data were compared with one-way analysis ofvariance (ANOVA) with post hoc Fisher's LSD test for multiplecomparisons. Not-normally distributed data were analyzed with parametrictests after log- or (double) square root-transformation if this resultedin a normal distribution. Comparison of proportions was performed usingFisher's exact tests. Continuous non-normally distributed data werecompared with non-parametric Mann-Whitney U tests. Two-sidedp-values<0.05 were considered statistically significant (Statview 5.0.1,JMP 8.0.1 and SPSS 22 were used). Data are presented as box plots withmedian, interquartile ranges and 10th and 90th percentiles or as barswith whiskers, representing means and standard error of the mean (SEM).ANOVA or Mann-Whitney p-values are presented in figure legends. Post-hocp-values<0.1 are plotted on the figures.

Study Approval

All animals were treated according to the Principles of LaboratoryAnimal Care (U.S. National Society for Medical Research) and the Guidefor Care and Use of Laboratory Animals (National Institutes of Health).The protocols for these animal studies had been approved by theInstitutional Ethical Committee for Animal Experimentation (projectnumber P051/2010 and P050/2015). The study protocol of the human studieshad been approved by the Institutional Review Board of the KU Leuven(ML1820, ML2707, ML4190, ML1094). Written informed consent was obtainedfrom the patients' closest family member and from healthy volunteers.

Example 1: Mice Study—Body Composition

We hypothesized that during critical illness, fat mobilized from excessadipose tissue can provide energy to vital organs more efficiently thanexogenous macronutrients, and that this might prevent lean tissuewasting. We tested this hypothesis in a centrally-catheterized mousemodel of cecal ligation and puncture (CLP)-induced septic criticalillness and in a human study. In lean and premorbidly obese mice, theeffect of 5 days of critical illness on body weight and composition,muscle wasting and weakness was compared, each with fasting andparenteral feeding. Additionally, in matched lean and overweight/obesecritically ill patients, we compared markers of muscle wasting in musclebiopsies of two muscle groups (musculus (m.) vastus lateralis and m.rectus abdominis) as well as muscle strength, quantified by the MedicalResearch Council (MRC) sum score.

Prior to CLP, body weight was significantly higher in obese than in leanmice (35.3±0.5 g vs. 29.4±0.6 g, p<0.0001). This was attributable to ahigher fat mass in obese compared to lean mice (9.0±0.6 g vs. 4.7±0.2 g,p<0.0001), whereas fat-free mass was equal in obese and lean mice(23.5±0.4 g vs. 22.7±0.4 g, p=0.2).

After 5 days of CLP-induced critical illness, all animals lost acomparable amount of body weight, hence body weight remained higher inobese vs. lean CLP mice (FIG. 1a-b ). Critical illness also resulted inloss of fat mass, but obese CLP mice lost more than double the amount offat mass over 5 days of illness than lean CLP mice (FIG. 1c-d ). In bothlean and obese CLP mice, the loss of body weight and fat mass wasunaffected by parenteral feeding (FIG. 1). Critical illness resulted ina loss of lean tissue in lean, but not in obese mice, as demonstrated bythe reduction in dry weight of isolated m. tibialis anterior and m.soleus (FIG. 2a-b ). This coincided with a reduced myofiber CSA of them. tibialis anterior in the lean, but not in obese CLP mice (FIG. 2c ).Consequently, mean muscle myofiber size was larger in obese CLP micethan lean CLP mice (FIG. 2c ). Fasting during critical illness tended tofurther reduce the dry muscle weight (FIG. 2a-b ), whereas theoccurrence of smaller myofibers was present in both fed and fastedanimals (FIG. 2c ).

Example 2: Mice Study—Markers of Skeletal Muscle Atrophy and Autophagy

We investigated whether less activation of atrophy pathways couldexplain the observed preservation of muscle mass and muscle fiber sizein obese CLP mice. Compared to lean healthy control mice, muscle proteincontent tended to be reduced in lean fed CLP mice (83.9±8.3 μg/mg vs.55.1±10.1 μg/mg, p=0.06) and was reduced in lean fasted CLP mice(50.4±11.1 μg/mg, vs. lean healthy controls, p=0.01). In contrast, obeseCLP mice preserved their muscle protein content (108.1±20.8 μg/mg vs.76.1±14.8 μg/mg in fed CLP mice p=0.8, and 63.5±6.6 μg/mg in fasted CLPmice p=0.1). Gene expression of markers of the ubiquitin-proteasomesystem, Fbxo32 and Trim63, were upregulated in lean and obese CLP mice(FIG. 3a-b ). Fasted lean CLP mice displayed a further increase inFbxo32 and Trim63 expression (FIG. 3a-b ). Activity of the proteolyticenzyme 20S-proteasome was unaffected by critical illness (FIG. 3c ). Incontrast, cathepsin activity was increased in lean CLP mice, whereasthis increase tended to be attenuated in obese CLP mice (FIG. 3d ).Compared to lean and obese healthy control animals, fasting furtherincreased the cathepsin activity both in lean and obese CLP mice (FIG.3d ).

Gene expression of Atg7 was elevated in both lean and obese CLP mice,but most pronounced in fasted lean CLP mice (FIG. 3e ). In contrast,Atg5 gene expression was only increased in fasted lean CLP mice (FIG. 3f). The LC3 protein ratio (LC3-II/LC3-I), a marker of autophagosomeformation, appeared unaffected after 5 days of critical illness (FIG. 3g). Protein levels of p62, used as a marker of insufficiently activatedautophagy, were elevated in CLP mice, irrespective of obesity or whetherthe mice were fasted or received parenteral feeding (FIG. 3h ).

To exclude the involvement of increased fibrosis or myostatin-associatedhypertrophy in the preservation of muscle mass, we quantified geneexpression of fibrogenic genes Collal and S100a4, muscle growthinhibiting factor Mstn, and hypertrophy marker Igf1. These markers werelargely unaffected by illness. However, fasted lean CLP micedemonstrated lower Col1a1 and higher Mstn gene expression levels thanhealthy mice and fasted obese CLP mice. Histological analysis of themuscle in lean and obese CLP mice indicated similar signs of fibrosis(63% and 71% respectively, p=0.6) and fasciitis (11% and 6%respectively, p=0.8). Also structural abnormalities (58% and 65%respectively, p=0.6) and signs of necrosis (16% and 6% respectively,p=0.3) were equally observed in lean and obese CLP mice.

Example 3: Mice Study—Ectopic Triglyceride Content

To determine whether an effect on lipid content might contribute to thepreservation of muscle mass in obese CLP mice, muscle triglyceridecontent was quantified. Whereas healthy lean and obese mice hadcomparable muscle triglyceride contents, muscle triglyceride content wasdecreased in lean CLP mice, irrespective of nutritional intake (FIG. 4a). In contrast, triglyceride content of the muscle was preserved in fedand fasted obese CLP mice (FIG. 4a ). Furthermore, muscle mass of m.tibialis anterior correlated significantly with muscle triglyceridecontent (R=0.498, p=0.0002).

Next, we investigated whether a comparable effect was present in theliver. Healthy lean and obese mice had comparable hepatic triglyceridecontents (FIG. 4b ), confirming the absence of potentially adversefeatures of a morbid obesity-associated liver steatosis. Livertriglyceride content was decreased in lean CLP mice, irrespective ofnutritional intake, whereas it was preserved in fed and fasted obese CLPmice (FIG. 4b ).

Example 4: Mice Study—Markers of Fatty Acid and Glycerol Metabolism

The observations of enhanced loss of fat mass (FIG. 1b ) andpreservation of ectopic (muscle and liver) fat (FIG. 4) in obese CLPmice, suggest that during CLP-induced critical illness, more fat wasmobilized from the adipose tissue of obese CLP mice. Therefore, wesubsequently quantified circulating levels of fatty acids and glyceroland markers of hepatic uptake and metabolism of these substrates. Serumfatty acid concentration was not different from controls in lean CLPmice. In contrast, in obese CLP mice, fatty acid serum concentration wasdecreased (obese healthy control mice 1384.4±221.3 μM vs. obese CLP mice804.9±76.8 μM; p=0.007) (FIG. 5a ). Hepatic gene expression of Cd36, afatty acid transporter, was markedly increased in obese (healthy,fasted-CLP and fed-CLP) mice compared to lean (healthy, fasted-CLP andfed-CLP) mice (FIG. 5b ). Hepatic gene expression of Acadl, the firstenzyme of β-oxidation, was comparable in lean, obese, healthy, and CLPmice (data not shown). However, hepatic gene expression of Hmgcs2,encoding for the mitochondrial enzyme that catalyzes the first step ofketogenesis, decreased in lean CLP animals (lean healthy control mice1.0±0.1 vs. lean CLP mice 0.6±0.1; p=0.01), whereas its expression wasunaltered in obese CLP mice (FIG. 5c ). Thus, obese CLP mice showedhigher Hmgcs2 gene expression than lean CLP mice. This difference ingene expression coincided with higher serum ketone body (3-HB)concentrations in obese CLP mice than in lean CLP mice (FIG. 5d ).

Healthy lean mice had lower serum glycerol concentrations than healthyobese mice. Whereas circulating glycerol was not altered by criticalillness in lean mice, glycerol serum concentrations in obese CLP micewere reduced after 5 days of critical illness (FIG. 6a ). Geneexpression of Aqp9, an aquaglyceroporin membrane channel that conductsglycerol into the liver, was unaltered (FIG. 6b ). However, geneexpression of Gk, encoding the rate-limiting enzyme in the hepaticconversion from glycerol to glucose, was higher in obese compared tolean mice (FIG. 6c ). Overall, these parameters were not affected by thenutritional intake, neither in lean nor in obese CLP mice (FIGS. 5 and6).

Example 5: Mice Study—Muscle Strength and Recovery from Fatigue

After 5 days of critical illness, only the lean but not the obese micelost m. EDL mass (FIG. 7a ). Lean and obese healthy control mice hadcomparable twitch tensions (39.2±1.9 mN vs. 43.9±4.6 mN; p=0.5), tetanictensions (213.3±9.5 mN vs. 203±15.4 mN; p=0.4) and fatigue recoveryrates (42% vs. 38%; p=0.2) (FIG. 7). Peak twitch tension was unalteredin lean and obese CLP mice (data not shown). However, lean CLP micedemonstrated a lower peaktetanic tension and a lower recovery fromfatigue than lean control mice, whereas obese CLP mice maintained peaktetanic tensions and the recovery from fatigue was comparable to obesehealthy control mice (FIG. 7b-c ). Compared to lean CLP mice, obese CLPmice tended to have higher peak tetanic tensions and displayed betterrecovery from fatigue (FIG. 7b-c ).

Example 6: Patient Study—Muscle Wasting and Weakness

We next assessed whether attenuation of muscle wasting and muscleweakness was also present in obese/overweight versus lean prolongedcritically ill patients. Myofiber CSA of the m. vastus lateralis wascomparable in lean and overweight/obese healthy volunteers. However,myofibers were significantly smaller in lean prolonged critically illpatients than in healthy volunteers, as illustrated by a shift to theleft in the histogram of myofiber size distribution (FIG. 8a ). Incontrast, overweight/obese critically ill patients maintained theirmyofiber size compared to healthy controls, which resulted in largermyofibers compared to lean critically ill patients (FIG. 8a ). Thesefindings were confirmed in a second set of postmortem m. rectusabdominis biopsies (FIG. 8b ). Furthermore, fewer overweight/obeseprolonged critically ill patients suffered from muscle weakness thanlean prolonged critically ill patients (12% vs. 24%: p=0.004).

In examples 1 to 6 we demonstrated in mice and humans that being obeseprior to becoming critically ill protected against muscle wasting andweakness. As compared with lean critically ill mice, obese mice showedbetter preservation of muscle mass and myofiber size, irrespective ofwhether they were fasted or received parenteral nutrition. Furthermore,obese CLP mice preserved their muscle strength. Obesity, but notnutrition during critical illness, attenuated the loss of lipids andmyofibrillary proteins, and increased mobilization and metabolization offat from adipose tissue. In human muscle biopsies of overweight/obeseprolonged critically ill patients, myofiber size appeared more preservedthan in lean patients. Moreover, fewer overweight/obese patientssuffered from muscle weakness than lean patients, assessed one weekafter admission to the ICU.

Critical illness is known to induce loss of muscle mass and thedevelopment of muscle weakness (Kress J P, Hall J B, 2014 NEJM,370(17):1626-35). Although multiple mechanisms underlying muscle wastingand weakness during critical illness have been identified, efficienttherapies preventing critical illness-associated muscle wasting andweakness remain elusive. Therefore, the finding that obesity not onlyprotected against lean tissue wasting but also against muscle weaknessduring critical illness is remarkable.

We observed increased markers of the ubiquitin-proteasome and theautophagy-lysosome pathway in muscle of critically ill mice. Obesitytended to attenuate increased cathepsin activity after 5 days ofcritical illness. Furthermore, whereas in lean critically ill mice,fasting induced a significant further increase in atrophy markers, thisfasting response was absent in obese critically ill mice. In addition tothe ubiquitin-proteasome pathway, also insufficiently activatedautophagy can play a key role in muscle wasting and the development ofmuscle weakness (Hermans et al, 2013 Lancet Respir Med 1(8):621-9).Insufficient autophagy activation is characterized by elevated p62protein levels and an inadequate rise in LC3-II/LC3-1 ratio. We observedp62 accumulation in the presence of an unaltered LC3-II/LC3-1 ratio andincreased expression of autophagy-related genes Atg5 and Atg7 in muscleof lean and obese CLP mice. Similarly to the findings for theubiquitin-proteasome pathway, only lean but not obese critically illanimals displayed an additional upregulation in autophagy genes inresponse to fasting. Histological analysis indicated presence of muscleabnormalities (such as myocyte necrosis, fibrosis and fasciitis) in ourmice model consistent with earlier human and rodent observations.However, the histological markers as well as gene expression offibrogenesis and muscle hypertrophy markers were not affected by thepresence of obesity during critical illness, suggesting that thesepathways did not contribute to the preservation of muscle mass in obesecritically ill mice. The maintenance of muscle proteins and storedectopic (muscle and liver) triglycerides in obese CLP mice suggests thatobese mice, in contrast to lean mice, may use other energy stores duringcritical illness. The observation that total body fat mass was morereduced during critical illness in obese compared to lean mice,concomitantly with the preservation of ectopic fat, indicates that morelipids were released from adipose tissue stores of obese CLP mice.Theoretically, sufficiently available circulating fatty acids andglycerol for energy consumption would reduce the need for utilization ofenergy substrates stored in vital organs, such as structural lipids andproteins. However, obese CLP mice did not display higher circulatingfatty acids and free glycerol than lean CLP mice. Possibly, we missed arise in circulating lipids on an earlier time point. On the other hand,obesity has been shown to influence the turnover rate of circulatingfatty acids and glycerol, and thus increased metabolization of thesesubstrates by the liver could have decreased their serum concentrations.

In our mouse study we indeed observed such signs of an elevated fattyacid and glycerol turnover rate in all obese mice, unaffected bynutrition or illness. The increase in circulating ketone bodies in obeseCLP mice further indicates enhanced fatty acid metabolism. Obese micethus appear to have a different metabolic response to prolonged criticalillness as compared with lean mice. Together, our findings may suggestthat obese critically ill mice preferentially use fat from adiposetissue, while lean critically ill mice may utilize ectopically storedlipids and proteins. Possibly, the combination of mobilizing excessstored triglycerides in adipose tissue, and enhanced metabolism of fattyacids and glycerol from these stores, prevents or decreases the use ofstored proteins and triglycerides in muscle tissue during criticalillness. Glycerol and fatty acid metabolism can indeed generate vitalenergy through the production of glucose and ketone bodies. In addition,ketone bodies may also directly be involved in the attenuation of musclewasting, comparable to what has been observed in pancreatic cancercachexia (Shukla S K et al, 2014 Cancer&Metabolism 2:18).

It was demonstrated earlier that administration of parenteral nutritionto critically ill patients could not attenuate muscle wasting and evenaggravated weakness (Hermans et al, 2013 Lancet Respir Med 1(8):621-9;Derde S et al, 2012 Crit Care Med 40(1):79-89). Our observations nowsuggest that the use of endogenous lipids released from the adiposetissue may counteract muscle wasting.

Example 7: Mice Study—Effect of Administration of D,L-3-Hydroxybutyrate

The observation that in contrast to lean mice, obese mice strikingly donot suffer from muscle wasting and weakness when critically ill and theypresent with higher serum levels of the ketone body 3-hydroxybutyrateduring illness, prompted us to assess whether the administration of3-hydroxybutyrate to lean critically ill mice could prevent musclewasting and weakness. Within the skeletal muscle, 3-hydroxybutyrate hasshown to be effectively used as energy source and was found to improvephysical endurance in highly trained athletes. Also, there is evidencethat ketone bodies could inhibit muscle atrophy. Therefore, wehypothesized that the administration of 3-hydroxybutyrate to leancritically ill mice could prevent muscle wasting and weakness.

We studied the effect of subcutaneous administration ofD,L-3-hydroxybutyrate sodium salt on muscle wasting and weakness in avalidated mouse model of prolonged critical illness evoked by sepsis(cecal ligation and puncture followed by resuscitation and intensivemedical care). The intervention was studied in the parenterally fed andin the fasted state.

Muscle function was quantified in isolated extensor digitorum longus(EDL) muscle. Critical illness in parenterally fed mice (PN) reduced theabsolute maximal force generated by EDL to 57% of healthy controls(p<0.0001) (FIG. 9). However, when parenterally fed critically ill micereceived subcutaneous twice daily a bolus of 75 mg ofD,L-3-hydroxybutyrate sodium salt (PN+3HB), maximal muscle forceimproved dramatically to 83% of healthy controls (p<0.0001) (FIG. 9). Incontrast, in fasted critically ill mice, twice dailyD,L-3-hydroxybutyrate sodium salt boluses of 75 mg (fasting+3HB)increased risk of death (FIG. 10) and in survivors reduced maximalmuscle force to 33% of the force of healthy control mice (p<0.0001)(FIG. 9).

Muscle wasting was evaluated by quantification of the dry weight ofisolated skeletal muscles. Muscle weight of the EDL muscle decreased inall critically ill mice, irrespective of hydroxybutyrate treatment ornutritional regime (1.9±0.3 mg for PN, 2.1±0.3 mg for PN+3HB, and2.0±0.4 mg for fasting+3HB as compared with 2.7±0.3 mg in healthycontrol mice; p<0.0001) (FIG. 11A). Also the weight of the largertibialis anterior muscle decreased significantly in all groups ofcritically ill mice as compared with healthy controls, againirrespective of hydroxybutyrate treatment and feeding regime (9.0±1.2 mgfor PN, 8.9±1.4 mg for PN+3HB, and 8.4±1.8 mg for fasting+3HB versus12.4±1.3 mg in healthy controls; p<0.0001) (FIG. 11B).

In a second experiment we compared the effect of a lipid-rich, ketogenicdiet (90% lipids, 10% glucose), with standard PN (35% lipids, 49%glucose, 16% proteins) on muscle wasting and weakness in our mouse modelof prolonged critical illness evoked by sepsis. Critical illness in PNmice reduced the absolute maximal force generated by EDL to 58% ofhealthy controls (p<0.0001), whereas mice on a lipid-rich diet (Lipid)presented with highly improved maximal force to 73% of healthy controls(p=0.04) (FIG. 12). Muscle dry weight of the EDL muscle decreased in allcritically ill mice, irrespective of nutritional regime (2.9±0.6 mg forPN, 2.9±0.6 mg for Lipid, as compared with 4.3±1 mg for healthycontrols; p<0.0001) (FIG. 13A). Also tibialis anterior dry weightdecreased similarly in all critically ill mice (9.6±mg for PN and10.2±1.8 mg for Lipid versus 12.7±3.4 mg in healthy controls; p<0.001)(FIG. 13B). The lipid-rich diet increased circulating 3-hydroxybutyrateto 0.8±0.6 mM (p<0.0001 compared to PN critically ill mice and healthycontrols) (FIG. 14). Adversely, livers of Lipid critically ill micecontained 7-times more triglycerides than PN critically ill mice andhealthy controls (p<0.0001) (FIG. 15). This unfavorable liver steatosislimits the therapeutic potential of a lipid-rich, ketogenic diet duringcritical illness.

In conclusion, daily supplementation of D,L-3-hydroxybutyrate toparenterally fed mice largely prevented muscle weakness but not musclewasting during prolonged sepsis-induced critical illness. A similarpreventive effect on muscle weakness but not wasting was observed withthe administration of a lipid-rich diet, but at the cost of unfavorableliver steatosis.

Example 8: Energy Experiment

To investigate whether there is any potential synergy in the effect onmuscle weakness of D,L3-hydroxybutyrate sodium salt (3HB) and theindividual macronutrient components of standard parenteral nutrition(lipids, proteins, glucose) we performed an additional animalexperiment. We again used our validated mouse model of prolonged (5days) critical illness evoked by sepsis (cecal ligation and puncturefollowed by fluid resuscitation and intensive medical care). Criticallyill mice received twice daily a bolus injection of 75 mg of 3HB combinedeither with standard total parenteral nutrition (3HB+TPN, mixture ofglucose, lipids and amino acids), a glucose infusion (3HB+GLUC), alipid-low-glucose infusion (3HB+LIP), or an amino-acids-low-glucoseinfusion (3HB+AA) [Table 1 for composition].

Muscle mass and function was quantified in isolated extensor digitorumlongus (EDL) muscle. Total EDL muscle weight decreased similarly in allcritically ill mice, irrespective of parenteral nutrition compositionwith which the 3HB was combined (FIG. 16A). In contrast, muscle forcewas affected differently among the ill groups (FIG. 16B). Mice in theTPN+3HB group reached 76% (212±14 mN) of the maximal muscle force ofhealthy controls (278±17 mN, p<0.002), similarly to our previousfindings. In contrast, the maximal force reached by the GLUC+3HB,LIPID+3HB and AA+3HB groups was significantly lower than the TPN+3HBgroup (p≤0.05) with respectively 62% (173±13 mN), 57% (158±16 mN) and56% (155±15 mN) of the maximal muscle force of the healthy controls(p<0.0001). Specific maximal muscle force, corrected for the total EDLweight, was comparable between TPN+3HB and healthy controls, whereas itwas lower than controls similarly in the GLUC+3HB, LIPID+3HB and AA+3HBgroups (FIG. 16C).

In conclusion, we could confirm that daily supplementation ofD,L-3-hydroxybutyrate (3HB) to total parenteral nutrition largelyprevented muscle weakness but not muscle wasting during prolongedsepsis-induced critical illness. Importantly, the improvement of muscleweakness with ketone supplementation was only observed when combinedwith total parenteral nutrition that comprised a balanced mixture ofglucose, lipids and amino acids (FIG. 16).

TABLE 1 Composition of the different forms of parenteral nutrition Dailydose D,L-3-hydroxybutyrate (mg) Glucose Lipids Amino acids sodium saltTPN + 3HB 672 192 213 150 GLUC + 3HB 672 — — 150 LIPID + 3HB 298 192 —150 AA + 3HB 298 — 213 150

1: A method of treatment for ameliorating or preventing critical illnessmyopathy (2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81), or criticalillness neuromyopathy (CINM) comprising administering to a patient inneed thereof an 3-hydroxybutyrate of the groups consisting of an3-hydroxybutyrate, its enantiomer (R)-3-hydroxybutyric acid,(S)-3-Hydroxybutyric acid or enantiomeric mixture, or a pharmaceuticallyacceptable or under food law acceptable salt, for instance(R)-3-hydroxybutyric sodium salt or sodium (S)-3-hydroxybutyrate, or apharmaceutically acceptable or under food law acceptable ester thereof,for instance (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. 2: The methodaccording to claim 1, whereby the treatment with the 3-hydroxybutyrateis carried out with a continuous or multiple dose regime at a dose rangeof 0.08 g/kg patient body weight to 4.13 g/kg patient body weight per 24hours. 3: The method according to claim 1, wherein the treatment withthe 3-hydroxybutyrate is carried out with a continuous or multiple doseregime at a dose range of 0.8 mmol/kg patient body weight to 39.7mmol/kg patient body weight per 24 hours. 4: The method according toclaim 1, wherein the treatment with the 3-hydroxybutyrate is carried outwith a continuous or bolus, parenteral or enteral dose range of 0.08g/kg to 4.13 g/kg patient body weight per 24 hours. 5: The methodaccording to claim 1, wherein the treatment with the 3-hydroxybutyrateis carried out with a continuous or bolus, parenteral or enteral doserange of 0.8 mmol/kg patient body weight to 39.7 mmol/kg patient bodyweight per 24 hours. 6: The method according to any one claim 1, whereinthe 3-hydroxybutyrate is administered to a patient at a daily dose ofabout 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6 mmol/kg to31.7 mmol/kg, more preferably of about 3.2 mmol/kg. 7: The methodaccording to any claim 1, wherein the 3-hydroxybutyrate is incombinational therapy formulated together and in individual dosageamounts or formulated separately and in individual dosage amounts with achemical energy providing macronutrient or caloric organic compoundcomprising at least one macro-nutrient member of one of the threemacronutrient groups or of two of the three macronutrient groups each orof each of the three macronutrient groups 1) a macronutrient groupconsisting of amino acid, peptide and protein or combination thereof and2) a macronutrient group consisting of fatty acid, glycerol, glycerideand triglyceride or combination thereof and 3) a macronutrient groupconsisting of monosaccharide, disaccharide, oligosaccharide andpolysaccharide or combination thereof.
 8. (canceled)
 9. (canceled) 10:The method according to claim 1, wherein the patient has a BMI under24.9.
 11. (canceled)
 12. (canceled) 13: The method according to claim 1,further comprising one or more pharmaceutically acceptable or under foodlaw acceptable adjuvants, carriers, excipients, and/or diluents. 14: Amethod of treatment for treating or preventing critical illness myopathy(2016/17 ICD-10-CM Diagnosis Code G72.81), critical illnesspolyneuropathy (2016/17 ICD-10-CM Diagnosis Code G62.81) or criticalillness neuromyopathy (CINM), comprising administering a pack orcomposition comprising an 3-hydroxybutyrate, its enantiomer(R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomericmixture, or a pharmaceutically or under food law acceptable salt, forinstance (R)-3-hydroxybutyric sodium salt or sodium(S)-3-hydroxybutyrate, or a pharmaceutically acceptable or under foodlaw acceptable ester thereof, for instance (R)-3-hydroxybutyl(R)-3-hydroxybutyrate and a macro nutrient mixture comprising at leastone macronutrient member of one of the three macronutrient groups or oftwo of the three macronutrient groups each or of each of the threemacronutrient groups 1) a macro nutrient of the group consisting ofamino acid, peptide and protein or combination thereof and 2) amacronutrient of the group consisting of fatty acid, glycerol, glycerideand triglyceride or combination thereof and 3) a macronutrient of thegroup consisting of monosaccharide, disaccharide, oligosaccharide andpolysaccharide or combination thereof.
 15. (canceled) 16: The methodaccording to claim 14, for preventing or ameliorating muscle weakness(2017 ICD-10-CM Diagnosis Code M62.81) evoked, induced or enhanced by acritical illness myopathy 2016/17 (ICD-10-CM Diagnosis Code G72.81) orcritical illness neuromyopathy (2016/17 ICD-10-CM Diagnosis Code G62.81)disorder. 17: The method according to claim 14, whereby the pack orcomposition comprises an 3-hydroxybutyrate, its enantiomer(R)-3-hydroxybutyric acid, (S)-3-Hydroxybutyric acid or enantiomericmixture, or a pharmaceutically acceptable or under food law acceptablesalt, for instance (R)-3-hydroxybutyric sodium salt or sodium(S)-3-hydroxybutyrate, or a pharmaceutically acceptable or under foodlaw acceptable ester thereof, for instance (R)-3-hydroxybutyl(R)-3-hydroxybutyrate and a macronutrient mixture comprising at leastone macronutrient member of one of the three macronutrient groups or oftwo of the three macro nutrient groups each or of each of the threemacro nutrient groups 1) a macronutrient group consisting of amino acid,peptide and protein or combination thereof and 2) a macronutrient groupconsisting of fatty acid, glycerol, glyceride and triglyceride orcombination thereof and 3) a macronutrient group consisting ofmonosaccharide, disaccharide, oligosaccharide and polysaccharide orcombination thereof. 18: The method according to claim 14, wherein said3-hydroxybutyrate and said macronutrient mixture are formulated togetherand in individual dosage amounts. 19: The method according to claim 14,wherein said 3-hydroxybutyrate and said macronutrient mixture areformulated separately and in individual dosage amounts. 20: The methodaccording to claim 14, wherein the treatment with 3-hydroxybutyrate isto be carried out with a continuous or multiple dose regime at a doserange of 0.08 g/kg patient body weight to 4.13 g/kg patient body weightper 24 hours. 21: The method according to claim 14, wherein thetreatment with 3-hydroxybutyrate is carried out with a continuous ormultiple dose regime at a dose range of 0.8 mmol/kg patient body weightto 39.7 mmol/kg patient body weight per 24 hours. 22: The methodaccording to claim 14, wherein the treatment with 3-hydroxybutyrate iscarried out with a continuous or bolus, parenteral or enteral dose rangeof 0.08 g/kg to 4.13 g/kg patient body weight per 24 hours. 23: Themethod according to claim 14, wherein the treatment with3-hydroxybutyrate is carried out with a continuous or bolus, parenteralor enteral dose range of 0.8 mmol/kg patient body weight to 39.7 mmol/kgpatient body weight per 24 hours. 24: The method according to claim 14,wherein the 3-hydroxybutyrate is administered to a patient at a dailydose of about 1.6 mmol/kg to 79.3 mmol/kg, preferably of about 1.6mmol/kg to 31.7 mmol/kg, more preferably of about 3.2 mmol/kg. 25: Themethod according to claim 14, wherein the 3-hydroxybutyrate is presentin said composition in an amount equivalent to 1-70 grams. 26.(canceled)
 27. (canceled) 28: The method according to claim 14, whereinthe 3-hydroxybutyrate is present in said composition in an amountequivalent to 0.05-10 grams.
 29. (canceled) 30: The method according toclaim 14, wherein said pack or composition is formulated for systemicadministration. 31: The method according to claim 14, without causing orwithout aggravating an hepato-pancreato-biliary disorder, withoutcausing or without aggravating fatty liver, or without causing orwithout aggravating nonalcoholic steatohepatitis (NASH) (2017 ICD-10-CMDiagnosis Code K75.81).
 32. (canceled)
 33. (canceled) 34: The methodaccording to claim 14, wherein the 3-hydroxybutyrate is(R)-3-hydroxybutyric acid or a pharmaceutically acceptable or under foodlaw acceptable ester thereof. 35: The method according to claim 14,wherein the 3-hydroxybutyrate is (S)-3-Hydroxybutyric acid orpharmaceutically acceptable or under food law acceptable ester thereof.36: The method according to claim 14, wherein the 3-hydroxybutyrate is(R)-3-hydroxybutyric sodium salt. 37: The method according to claim 14,wherein the 3-hydroxybutyrate is sodium (S)-3-hydroxybutyrate. 38: Themethod according to claim 14, wherein the 3-hydroxybutyrate is theD-β-hydroxybutyrate ester, (R)-3-hydroxybutyl (R)-3-hydroxy-butyrate.39: The method according to claim 14, further comprising apharmaceutically acceptable or under food law acceptable carrier. 40:The method according to claim 14, whereby said pack or composition has atotal calorie content between 16-106% of the calculated caloric targetfor intensive care (ICU) patients. 41: The method according to claim 14,whereby said pack or composition has a total calorie content between 200to 2000 kcal/l yet more preferable between 900 to 1400 kcal/l, yet morepreferable 900 to 1300 kcal/l, 1100 to 1200 kcal/l. 42: The methodaccording to claim 14, whereby said pack or composition has a caloriecontent of monosaccharide, disaccharide, oligosaccharide, polysaccharidefatty acid, glycerol, glyceride and/or triglyceride between 0 to 1300kcal/l, between 600 to 1300 kcal/l, yet more preferable between 700 to1200 kcal/l, yet more preferable 800 to 1100 kcal/l, 900 to 1000 kcal/l.43: The method according to claim 14, whereby said composition has acalorie content of amino acid, peptide and/or protein between 0 to 330kcal/l, between 20 to 330 kcal/l, yet more preferable between 50 to 300kcal/l, yet more preferable 100 to 250 kcal/l and most preferable 150 to200 kcal/l, for instance for a use of delivering between 0 and 2g/kg/day.
 44. (canceled)
 45. (canceled) 46: The method according toclaim 14, whereby the fatty acid, glycerol, glyceride and/ortriglyceride provide between 20 to 80%, yet more preferable 25 to 45%and most preferable 30 to 40% of the total calorie content of saidcomposition. 47: The method according to claim 14, for use in atreatment of a patient with a BMI under 24.9.
 48. (canceled) 49.(canceled)